US4571428A - 6-Substituted-4-hydroxy-tetrahydropyran-2-ones - Google Patents
6-Substituted-4-hydroxy-tetrahydropyran-2-ones Download PDFInfo
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- US4571428A US4571428A US06/512,163 US51216383A US4571428A US 4571428 A US4571428 A US 4571428A US 51216383 A US51216383 A US 51216383A US 4571428 A US4571428 A US 4571428A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- This invention relates to a process for preparing organic compounds, and more specifically for preparing 6-substituted-4-hydroxy-tetrahydropyran-2-ones, as well as intermediates, per se in the process.
- This invention provides a novel process for the preparation of trans olefins of the formula I: ##STR1## wherein R is: a phenyl structure of formula A: ##STR2## in which each of the R a , R b and R c is independently
- R d is any of hydrogen, C 2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C 1-3 alkyl, C 1-9 alkyl, cinnamyl, C 1-4 haloalkyl, allyl, cycloalkyl-C 1-3 alkyl, adamantyl-C 1-3 alkyl, or substituted phenyl-C 1-3 alkyl in each of which the substituents are selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 haloalkyl;
- R 3 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R 2 and R 3 is trifluoromethyl, not more than one of R 2 and R 3 is phenoxy, and not more than one of R 2 and R 3 is benzyloxy,
- R 1 is hydrogen, C 1-3 alkyl, fluoro, chloro or benzyloxy,
- R 4 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
- R 5 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R 4 and R 5 is trifluoromethyl, not more than one of R 4 and R 5 is phenoxy, and not more than one of R 4 and R 5 is benzyloxy,
- R 4 ' is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and
- R 5 ' is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the proviso that not more than one of R 4 ' and R 5 ' is trifluoromethyl, not more than one of R 4 ' and R 5 ' is phenoxy and not more than one of R 4 ' and R 5 ' is benzyloxy
- R 2 ' is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
- R 3 ' is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy with the provisos that not more than one of R 2 ' and R 3 ' is trifluoromethyl, not more than one of R 2 ' and R 3 ' is phenoxy, and not more than one of R 2 ' and R 3 ' is benzyloxy, and ##STR7## wherein R 6 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, benzyl or M, wherein M is a pharmaceutically acceptable cation; *
- the compounds of formula I constitute 3 classes of compounds depending on the nature of R, namely (1) compounds IA, where R is of formula A, IB where R is of formula B, and of IC when R is of formula C. Within the main classes, subclass can be seen, such as type IB-1 where R o +R o is an alkadienyl chain and type IB-2 where R o +R o is a alkylene chain; types IC-1 and IC-2 depending upon whether R o is at position-1 or-3.
- Compounds IA are known and described in U.S. Pat. No. 4,308,378 (issued Dec. 29, 1981) wherein the compounds are disclosed to be useful as anti-hypercholesteremic agents.
- Compounds IB are disclosed in pending application Ser. No. 460,600 filed Jan. 24, 1983.
- Compounds IC are disclosed in pending application Ser. No. 443,668 filed Nov. 22, 1982.
- Compounds IB and IC are also useful as anti-hypercholesteremic agents as they are inhibitors of cholesterol biosynthesis in the manner of the known products compactin and mevinolin and are therefore useful in the treatment of atherosclerosis, as described in said applications.
- halogen and halo as used in the definition of compounds IA is intended to include fluoro and chloro.
- An embodiment of this invention is a multi-step process for the preparation of compounds I, which process may conveniently be represented by Reaction Scheme A, below, wherein R is as defined above.
- R 6' is the same as R 6 when it is not hydrogen or M and P' is a protecting (or masking) group for a hydroxy function.
- the final products I are shown as compounds I' (where Z is of type II and R 6 is R 6' , I" where R 6 ⁇ H or M, and I'" where Z is of type III. ##STR8##
- Another interesting embodiment of this invention is the preparation of compounds H by reaction of an aldehyde (compound G) with a reagent furnishing the moiety
- reaction (process g) provides the trans isomer product (H) in high yields. It is also particularly interesting that the above reaction scheme provides the di-protected product (G) in high yields as a single diastereo isomer. Accordingly, each of the process steps b) to h 4 and the reaction products thereof, individually and in combination, constitute embodiments of this invention.
- phloroglucinol (Compound A) is reduced to 1,3,5-trihydroxycyclohexane (a compound B).
- the reduction may be accomplished by conventional means for reducing an aromatic compound to its saturated analog.
- a convenient method of carrying out process (a) is by hydrogenation under moderate pressure, e.g., from about 15 to 75 psi, such as 50 psi, in the presence of a hydrogenation catalyst, e.g., Raney Nickel or 5% rhodium on alumina at moderate temperatures, e.g., 20° to 80° C., such as 50° C., under essentially anhydrous conditions, in an inert medium, e.g., a lower alcohol, e.g., ethanol, or acetic acid 15% in ethanol.
- moderate pressure e.g., from about 15 to 75 psi, such as 50 psi
- a hydrogenation catalyst e.g., Raney Nickel or 5% rhodium on alumina
- a compound B is converted to a corresponding compound C by conversion of two of the hydroxy functions to protected forms.
- Process (b) may be accomplished by reacting a compound B with at least 2 equivalents thereof of a protecting group-bearing reagent of the formula II:
- P' is as defined above and L is a leaving group
- an acid acceptor e.g., imidazol
- an inert medium e.g., a liquid amide, such as dimethyl formamide (DMF) at moderate temperatures, e.g., from about 5° to 40°, under essentially anhydrous conditions.
- DMF dimethyl formamide
- the preferred compound II is chloro-diphenyl-t-butylsilane.
- Leaving groups are well known in the art, and include higher halo, i.e., chloro, bromo, or iodo, preferably chloro, and alkyl and aryl sulfonyl, radicals, e.g., C 1 -C 6 alkyl or phenyl which may be substituted or mono-substituted by a C 1 -C 4 alkyl, such as p-toluene sulphonyl.
- halo i.e., chloro, bromo, or iodo, preferably chloro
- alkyl and aryl sulfonyl radicals, e.g., C 1 -C 6 alkyl or phenyl which may be substituted or mono-substituted by a C 1 -C 4 alkyl, such as p-toluene sulphonyl.
- Suitable protective groups P' include (1) tri-substituted silyl radicals have at least 2, and preferably 3 bulky radicals, i.e. radicals selected from the group consisting of (a) tertiary alkyl (C 4 to C 8 ) groups especially t-butyl, and (b) aryl, preferably phenyl which may be unsubstituted or substituted by up to 2 (preferably 0 or 1) of any of lower alkyl (C 1 -C 4 ), chloro, nitro, trifluoromethyl, or mono-substituted in the para-position by phenyl or benzyl (which may be unsubstituted or in turn substituted by one or two of such groups as mentioned above, especially at the para-position; or (2) benzyl which may be unsubstituted or substituted by one or two (preferably only one, and at the para-position) of lower alkoxy (C 1 to 4) e.g., methoxy, chloro,
- process (c) the free hydroxy function of a compound C is oxidized to a carbonyl function to obtain a corresponding compound D.
- the oxidation may be carried out by the conventional manner for oxidizing a hydroxy to a carbonyl function.
- a convenient method of accomplishing process (C) is to treat a compound C with pyridinium chlorochromate, under essentially anhydrous conditions by employing molecular sieves, at moderate temperatures, e.g., from 20° to 60° C., such as 20° to 30° C., in an inert medium, such as a chlorinated lower alkane, e.g., methylene chloride, i.e. dichloromethane.
- a compound D is converted to its corresponding 7-member-ring lactone (a compound E), by a Baeyer-Villiger oxidation employing m-chloroperbenzoic acid and an inorganic base such as anhydrous sodium bicarbonate, under essentially anhydrous conditions at moderate temperatures, e.g. from about 20° to 100° C., such as at the reflux temperature of the mixture, in an inert medium, e.g., a chlorinated lower alkane, such as methylene chloride. It is convenient to subject the mixtures to ultrasonic radiation, but this is not essential.
- a compound E (lactone) is opened by reacting with an alcohol of the formula R 6' --OH, in which R 6' is as defined above, in the presence of a catalytic amount, e.g. 1%, of an acid, e.g., trifluoroacetic acid, acetic acid or hydrogen chloride in an inert medium, to yield the corresponding 6-hydroxyhexanoic acid ester (a compound F).
- a catalytic amount e.g. 1%
- an acid e.g., trifluoroacetic acid, acetic acid or hydrogen chloride
- an inert medium e.g., a catalytic amount, e.g. 1%
- an acid e.g., trifluoroacetic acid, acetic acid or hydrogen chloride
- a compound F 6-hydroxyhexanoic acid ester
- Preferred alcohols include methanol, ethanol and isopropanol. Elevated temperatures may be employed, e.g. 40° to
- a compound F is oxidized to its corresponding compound G.
- the reaction may be carried out in the conventional manner for oxidizing a primary alcohol to an aldehyde.
- a convenient method is by employing pyridinium chlorochromate under essentially anhydrous conditions in an inert medium, e.g., a chlorinated lower alkane, such as methylene chloride, at moderate temperatures, e.g., 20° to 50° C., conveniently at room temperature (20° to 30° C.). It is preferred to include molecular sieves in the reaction mixture.
- R is as defined above, and R w is an aryl radical.
- the reaction is conveniently carried out in an inert medium, e.g., a cyclic ether such as tetrahydrofuran at reduced temperatures, e.g. -15° to +5° C., such as -10° to 0° C.
- the reagent is prepared by treating a compound IV: ##STR10## in which R and R w are as defined above and Q is a higher halo (having an atomic weight of from about 34 to 120), e.g., chloro, bromo or iodo, with a strong base, such as an alkali metal salt of a hydrocarbon, e.g., n-butyl lithium, in an inert medium, such as a cyclic ether, at reduced temperatures, e.g., from about -15° to 0° C., e.g., about -10° C.
- a strong base such as an alkali metal salt of a hydrocarbon, e.g., n-butyl lithium
- an inert medium such as a cyclic ether
- R w is preferably phenyl which is unsubstituted or substituted by one or two lower alkyl (C 1 -C 4 ) or chloro substituents.
- a compound H is deprotected to the corresponding compound I'.
- the protecting group is a silyl-type
- acid treatment is employed, e.g., using a mixture of at least equal (e.g. 2 times) molar portions of acetic acid and tetrabutylammonium fluoride (TBAF) in THF, methanolic HCl, or fluoride anion reagents.
- Moderate temperatures may be employed, e.g., from about 20° to 60°, e.g., 20° to 30° C.
- the protecting group is of the benzyl-type
- deprotection is achieved by reductive hydrogenation, by methods known in the art.
- a compound I' i.e. the deprotected form of a compound H
- aqueous alkali metal base e.g., sodium hydroxide
- a watermiscible co-solvent e.g. dioxane
- R 6 is hydrogen
- R 6 M
- conventional means e.g., by acidifying with dilute hydrochloric acid.
- an inert medium e.g., an aromatic hydrocarbon such as toluene
- a compound H may be directly converted to its corresponding compound I'" by carrying out the procedure of process h 1 and heating e.g. at about 80° to 140°, e.g. at the refluxing temperature of the reaction medium, i.e. process h 4 .
- Reagents and starting materials described herein e.g., compounds A and B are known and obtainable by known means, or where not known, may be obtained by adaptation of methods reported in the literature for the preparation of known analogs; some compounds being commercially available.
- the final products and intermediate compounds described herein may be recovered and refined, where such is desired, by conventional means, such as by crystallization, distillation or chromatographic techniques such as column or thin layer chromatography, e.g., silica gel column chromatography.
- the reaction mixture is then filtered on celite, the filtrate retained, and the solids washed with ethanol.
- the combined filtrate and washes are concentrated by evaporating to a small volume, to which 100 ml of acetone is added resulting in a clear solution, which is allowed to stand at room temperature, from which 7 g of cis product of this step crystallizes out--m.p. 181°.
- Mixed (cis and trans) product can be recovered from the mother liquor by first concentrating it, then taking up in 50 ml of acetone plus enough methylene chloride to re-dissolve, and allowing product to crystallize out.
- This mixed product can be treated in the same manner as the compound B', in step B below and the product can then be used to prepare compound D via step C.
- Step B cis-1,3-di-(diphenyl-t-butyl-siloxy)-5-hydroxy-cyclohexane (a compound C) ##STR13##
- Step C cis-3,5-di-(diphenyl-t-butylsiloxy) cyclohexan-1-one (a compound D).
- Step D cis-2-oxy-4,6-di(diphenyl-t-butylsiloxy)cycloheptanone*, (a compound E) ##STR15##
- the product shows the following characteristics on analysis: IR(CHCl 3 ): 3048, 2997, 2949, 2865, 1901, 1834, 1739 (lactone C ⁇ O), 1591, 1472, 1432, 1385, 1272, 1190, 1109, 1072, 1011, 938, 868 and 795 cm -1 .
- Step E methyl erythro-3,5 di-(diphenyl-t-butylsiloxy)-6-hydroxy-hexanoate (a compound F).
- Step F Methyl erythro-3,5-di-(diphenyl-t-butylsiloxy)-6-oxo-hexanoate a (compound G).
- Step A (E)-Methyl erythro-3,5-di-(diphenyl-t-butylsiloxy)-7-(2'-[4"-fluorophenyl]naphth-1'-yl)hept-6-enoate (a compound I').
- Step B Sodium trans-3,5-dihydroxy-7-(2'-[4"-fluorophenyl]-napht-1-yl)hept-6-enoate
- Step A (E)-Methyl-erythro-7-[1'-methyl-3'-(4"-fluorophenyl)indol-2'-yl]-3,5 di-(diphenyl-t-butylsiloxy)hept-6-enoate
- Step B (E)-sodium erythro-7-[1'-methyl-3-(4"-fluorophenyl)indol-2'-yl] 3,5-dihydroxyhept-6-enoate
Abstract
Description
--CH═CH--R
P'--L (II)
R--CH═P (R.sup.w).sub.3
Claims (7)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/512,163 US4571428A (en) | 1983-07-08 | 1983-07-08 | 6-Substituted-4-hydroxy-tetrahydropyran-2-ones |
US06/771,809 US4841071A (en) | 1983-07-08 | 1985-09-03 | 6-substituted-4-hydroxy-tetrahydropyran-2-ones |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/512,163 US4571428A (en) | 1983-07-08 | 1983-07-08 | 6-Substituted-4-hydroxy-tetrahydropyran-2-ones |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/771,809 Division US4841071A (en) | 1983-07-08 | 1985-09-03 | 6-substituted-4-hydroxy-tetrahydropyran-2-ones |
Publications (1)
Publication Number | Publication Date |
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US4571428A true US4571428A (en) | 1986-02-18 |
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Application Number | Title | Priority Date | Filing Date |
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US06/512,163 Expired - Lifetime US4571428A (en) | 1983-07-08 | 1983-07-08 | 6-Substituted-4-hydroxy-tetrahydropyran-2-ones |
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0244364A2 (en) * | 1986-04-30 | 1987-11-04 | Sandoz Ag | Preparation of olefinic compounds |
WO1988001997A2 (en) * | 1986-09-10 | 1988-03-24 | Sandoz Ag | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals |
US4792614A (en) * | 1987-08-05 | 1988-12-20 | American Home Products Corporation | Substituted furans as inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase |
US4812583A (en) * | 1987-09-11 | 1989-03-14 | American Home Products Corporation | Substituted acyloxyalkylphenylethylene inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase |
US4822799A (en) * | 1988-01-27 | 1989-04-18 | Sandoz Pharm. Corp. | Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals |
US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
US4977279A (en) * | 1987-12-08 | 1990-12-11 | Hoechst Aktiengesellschaft | Process for the preparation of optically active 3-demethylmevalonic acid derivatives, and intermediates |
EP0562643A2 (en) * | 1988-10-13 | 1993-09-29 | Sandoz Ag | 7-Substituted-hept-6-enoic and -heptanoic acids and derivatives thereof |
US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
US5354772A (en) * | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
WO2001092223A1 (en) * | 2000-05-26 | 2001-12-06 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of indole derivatives and intermediates of the process |
US20090082418A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched fluvastatin |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2628244A (en) * | 1950-12-07 | 1953-02-10 | Dow Corning | Trialkylsilylcyclohexanols and preparation thereof |
US4424392A (en) * | 1982-03-24 | 1984-01-03 | Union Carbide Corporation | Aldehyde containing hydrolyzable silanes |
-
1983
- 1983-07-08 US US06/512,163 patent/US4571428A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2628244A (en) * | 1950-12-07 | 1953-02-10 | Dow Corning | Trialkylsilylcyclohexanols and preparation thereof |
US4424392A (en) * | 1982-03-24 | 1984-01-03 | Union Carbide Corporation | Aldehyde containing hydrolyzable silanes |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5354772A (en) * | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
EP0244364A2 (en) * | 1986-04-30 | 1987-11-04 | Sandoz Ag | Preparation of olefinic compounds |
EP0244364A3 (en) * | 1986-04-30 | 1992-04-01 | Sandoz Ag | Preparation of olefinic compounds |
WO1988001997A2 (en) * | 1986-09-10 | 1988-03-24 | Sandoz Ag | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals |
WO1988001997A3 (en) * | 1986-09-10 | 1988-04-07 | Sandoz Ag | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals |
EP0265640A2 (en) * | 1986-09-10 | 1988-05-04 | Sandoz Ag | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals |
EP0265640A3 (en) * | 1986-09-10 | 1988-05-18 | Sandoz Ag | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals |
US4792614A (en) * | 1987-08-05 | 1988-12-20 | American Home Products Corporation | Substituted furans as inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase |
US4812583A (en) * | 1987-09-11 | 1989-03-14 | American Home Products Corporation | Substituted acyloxyalkylphenylethylene inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase |
US4977279A (en) * | 1987-12-08 | 1990-12-11 | Hoechst Aktiengesellschaft | Process for the preparation of optically active 3-demethylmevalonic acid derivatives, and intermediates |
US4822799A (en) * | 1988-01-27 | 1989-04-18 | Sandoz Pharm. Corp. | Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals |
EP0562643A2 (en) * | 1988-10-13 | 1993-09-29 | Sandoz Ag | 7-Substituted-hept-6-enoic and -heptanoic acids and derivatives thereof |
EP0562643A3 (en) * | 1988-10-13 | 1994-05-18 | Sandoz Ag | 7-substituted-hept-6-enoic and -heptanoic acids and derivatives thereof |
US5457227A (en) * | 1992-03-27 | 1995-10-10 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibitors |
US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
US5594153A (en) * | 1992-03-27 | 1997-01-14 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
WO2001092223A1 (en) * | 2000-05-26 | 2001-12-06 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of indole derivatives and intermediates of the process |
US20030166946A1 (en) * | 2000-05-26 | 2003-09-04 | Annemarie Wolleb | Process for the preparation of indole derivatives and intermediates of the process |
US6743926B2 (en) | 2000-05-26 | 2004-06-01 | Ciba Specialty Chemicals Corporation | Process for the preparation of indole derivatives and intermediates of the process |
US20040176614A1 (en) * | 2000-05-26 | 2004-09-09 | Annemarie Wolleb | Process for the preparation of indole derivatives and intermediates of the process |
US20090082418A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched fluvastatin |
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